SENCAR mice are markedly susceptible to two-stage skin carcinogenesis compared to BALB/c mice. Susceptibility is not due to differences in metabolism of polycyclic armatic hydrocarbons between SENCAR and more resistant strains. Sensitivity appears to be determined by the target tissue since SENCAR, but not BALB/c, skin grafted to nude mice developed papillomas at a high frequency after initiation and promotion. DNA repair capacity, studied by host cell reactivation, utilizing ultraviolet light-irradiated herps simplex virus, was similar in cultured epidermal cells of BALB/c and SENCAR. SENCAR cells have a greater binding capacity for epidermal growth factor than BALB/c cells, but the increased binding in response to retinoic acid and the rapid decrease after phorbol ester exposure are similar in the two strains. Expression of endogenous xenotropic type C proviral sequences occurs more readily in BALB/c. The frequency of spontaneous and carcinogen-induced, differentiation-resistant foci in vitro is greater in SENCAR than in BALB/c epidermal cells. these results suggest that susceptibility for skin carcinogenesis in SENCAR mice is a property of the skin itself and has no clear relation to DNA excision repair, endogenous virus expression, or EGF receptors.